The Glucoregulatory and Liporegulatory Peptide Hormones

描述（由申请人提供）：1.84亿美国人超重，其中4700万人患有代谢综合征，一组2型糖尿病，心脏病，肝病，血管疾病等。特异性目标1测试了新的假设，即它们是由导致肥胖的多余脂质分配受损造成的。当患有先天性瘦素抵抗的大鼠患上肥胖和代谢综合征时，它们的器官会因脂肪毒性脂肪酸衍生物（FA）而超载，而这些脂肪酸通常局限于脂肪细胞。在瘦素应答大鼠中，肥胖引起的高瘦素血症保护非脂肪组织免受异位脂质沉积，方法是通过下丘脑限制多余卡路里摄入的作用，将多余的卡路里分配到脂肪细胞储存空间，并通过直接刺激非脂肪组织中未利用的FA氧化。缺乏瘦素的作用会导致异位脂质沉积、受影响组织的功能损害（脂肪毒性）和脂质诱导的细胞凋亡增加。由此导致的器官衰竭在临床上与代谢综合征相同。虽然代谢综合征的最佳治疗方法是摄入不超过热量消耗的卡路里，但预防和逆转这一现代瘟疫的新药理学策略正在出现。具体目标2具有同样深远的公共卫生影响。我们观察到，瘦素化的胰岛移植到胰岛素缺乏的酮症酸中毒糖尿病大鼠体内后，可以在没有免疫抑制和功能的情况下存活至少一年，而未瘦素化的胰岛在3周内失去所有功能。降脂如何保护正常细胞免受致命的环境伤害是临床医学的巨大潜在兴趣。阐明它们一年存活一年的机制不仅可能推进1型糖尿病和其他器官移植治疗疾病的“治愈”，而且可能为对抗其他细胞破坏性临床疾病提供新的保护武器。器官中的脂肪酸（FA）水平可能影响其在各种类型损伤中的生存能力。我们的实验室已经证明，瘦素，一种脂肪细胞激素，当热量摄入过多时，通过将暴饮暴食引起的多余脂肪分配到脂肪细胞中，可以防止器官中的高FA水平。当分配受损时，FA溢出引起代谢综合征。我们还发现，通过降低FA，我们可以使细胞抵抗各种有害事件。胰岛移植的fa消耗使它们能够抵抗排斥反应。使用去fa胰岛，我们已经能够“治愈”胰岛素缺乏型糖尿病大鼠约1年而不产生免疫抑制。

DESCRIPTION (provided by applicant): 184 million Americans are overweight and 47 million of these have the metabolic syndrome, a cluster of type 2 diabetes, heart disease, liver disease, blood vessel disease, etc. Specific Aim 1 tests the novel hypothesis that they result from impaired partitioning of the surplus lipids that caused obesity. When rats with congenital leptin resistance develop obesity and metabolic syndrome, their organs become overloaded with lipotoxic derivatives of fatty acids (FA), which normally are confined to fat cells. In leptin-responsive rats obesity-induced hyperleptinemia protects nonadipose tissues from ectopic lipid deposition by partitioning surplus calories into the adipocyte storage space through hypothalamic actions that limit the intake of surplus calories and through direct stimulation of oxidation of unutilized FA in nonadipose tissues. Lack of leptin action causes ectopic lipid deposition, functional impairment of the affected tissues (lipotoxicity), and increased lipid-induced apoptosis. The resulting organ failure is clinically identical to the metabolic syndrome. While the best treatment for metabolic syndrome is the intake of calories not exceeding caloric expenditure, new pharmacologic strategies for preventing and reversing this modern plague are emerging. Specific Aim 2 has equally far-reaching public health implications. We have observed that leptinized islets can survive without immuno suppression and function for at least a year when transplanted into insulin-deficient ketoacidotic diabetic rats, whereas unleptinized islets lose all function within 3 weeks. How lipid-lowering protects normal cells against lethal environmental insults is of enormous potential interest in clinical medicine. Elucidation of the mechanism of their year-long survival for a year may not only advance "cure" of Type 1 diabetes and other disorders treated by organ transplantation, but may lead to novel protective weapons against other cytodestructive clinical disorders. The fatty acid (FA) levels in organs may influence their ability to survive various types of injury. Our lab has shown that leptin, an adipocyte hormone, prevents high FA levels in organs by partitioning the excess caused by overeating into fat cells when caloric intake is excessive. When partitioning is impaired, FA spillover causes metabolic syndrome. We also find that by lowering FA, we can make cells resistant to various noxious events. FA-depletion of pancreatic islet transplants makes them resistant to rejection. Using FA-depleted islets we have been able to "cure" insulin-deficient diabetes in rats for ~1 year without immunosuppression.